Indocyanine Green Lymphography, Lymphoscintigraphy, and Genetic Analysis in Nonsyndromic Primary Lymphedema: The Distal Dermal Backflow Grading System and the Print Sign

Abstract

Background Investigating correlations between clinical, instrumental, and genetic features of primary lymphedema (PL) with the aim to facilitate the diagnosis, the staging, and the management of this subgroup of patients.

Methods A prospective observational study was conducted from September 2016 to May 2018, including patients with diagnosis of nonsyndromic PL. All patients underwent a lymphoscintigraphic rest-stress test, an indocyanine green (ICG) lymphographic test, and a genetic test from sputum sample.

Results A total of 20 patients were enrolled in the study and 44 limbs were examined. The totality of clinically affected limbs (32/44) showed lymphographic and lymphoscintigraphic abnormalities. Concerning clinically healthy limbs (12/44), an abnormal pattern was demonstrated in 33.3% of ICG lymphographic test and 75% of lymphoscintigraphy. Regarding lymphography findings, the most frequent pattern was the distal dermal backflow (DDB). We distinguished four grades of DDB, which correlates with clinical and lymphoscintigraphic features. Furthermore, we found a new lymphographic alteration consisting of fluorescence appearing distally to the injection site of ICG, including fingers/toes and palmar/plantar surface of the hand and of the foot. This alteration, called “print sign,” seems to be typical of DDB pattern PL. Genetic test did not help us make any etiological diagnosis.

Conclusion To our knowledge, this is the first study about PL comparing clinical, ICG lymphographic, lymphoscintigraphic, and genetic findings. As expected, all clinically affected limbs showed abnormalities in ICG lymphographic and lymphoscintigraphic tests. In opposition to what has previously been reported, also clinically healthy limbs showed lymphographic and lymphoscintigraphic alterations and this could suggest the existence of a subclinical form of PL. We proposed a grading of the DDB pattern, which correlates with clinical and lymphoscintigraphic features. Furthermore, we have described a new lymphographic alteration that seems to be typical of DDB pattern PL, the “print sign.”

Keywords

primary lymphedema - idiopathic lymphedema - lymphography

Ethical Statement

No founding sponsor had a role in the collection of the data, in the writing of the manuscript, and in the decision to publish the results. Written informed consent was obtained from the patient.

Authors’ Contributions

The authors have seen and agreed to the submitted version of the paper. All persons who meet authorship criteria are listed as authors, and all authors certify that they have participated sufficiently in the work to take public responsibility for the content. Furthermore, each author certifies that this material or similar material has not been and will not be submitted to or published in any other publication before.

• References

• 1 Allen EV. Lymphedema of the extremities. Arch Intern Med (Chic) 1934; 54 (04) 606-624
• 2 The diagnosis and treatment of peripheral lymphedema: 2016 Consensus Document of the International Society of Lymphology. Lymphology 2016; 46: 1-11
• 3 M. Cossu. Epidemiologia. Giornale Italiano di Medicina Riabilitativa. 2008; 22 (03) 235-236
• 4 Rockson SG, Rivera KK. Estimating the population burden of lymphedema. Ann N Y Acad Sci 2008; 1131 (01) 147-154
• 5 Cooper G, Bagnall A. Prevalence of lymphoedema in the UK: focus on the southwest and West Midlands. Br J Community Nurs 2016; 21 (suppl): S6-S14
• 6 Deng J, Radina E, Fu MR. , et al. Self-care status, symptom burden, and reported infections in individuals with lower-extremity primary lymphedema. J Nurs Scholarsh 2015; 47 (02) 126-134
• 7 Dale RF. The inheritance of primary lymphoedema. J Med Genet 1985; 22 (04) 274-278
• 8 Northup KA, Witte MH, Witte CL. Syndromic classification of hereditary lymphedema. Lymphology 2003; 36 (04) 162-189
• 9 Connell FC, Gordon K, Brice G. , et al. The classification and diagnostic algorithm for primary lymphatic dysplasia: an update from 2010 to include molecular findings. Clin Genet 2013; 84 (04) 303-314
• 10 Brouillard P, Boon L, Vikkula M. Genetics of lymphatic anomalies. J Clin Invest 2014; 124 (03) 898-904
• 11 Michelini S, Vettori A, Maltese PE. , et al. Genetic screening in a large cohort of Italian patients affected by primary lymphedema using a next generation sequencing (NGS) approach. Lymphology 2016; 49 (02) 57-72
• 12 Connell FC, Ostergaard P, Carver C. , et al; Lymphoedema Consortium. Analysis of the coding regions of VEGFR3 and VEGFC in Milroy disease and other primary lymphoedemas. Hum Genet 2009; 124 (06) 625-631
• 13 O'Donnell Jr TF, Rasmussen JC, Sevick-Muraca EM. New diagnostic modalities in the evaluation of lymphedema. J Vasc Surg Venous Lymphat Disord 2016; 5 (02) 261-273
• 14 Roman MM, Barbieux R, Nogaret JM, Bourgeois P. Use of lymphoscintigraphy to differentiate primary versus secondary lower extremity lymphedema after surgical lymphadenectomy: a retrospective analysis. World J Surg Oncol 2018; 16 (01) 75
• 15 Yamamoto T, Yoshimatsu H, Narushima M, Yamamoto N, Hayashi A, Koshima I. Indocyanine green lymphography findings in primary leg lymphedema. Eur J Vasc Endovasc Surg 2015; 49 (01) 95-102
• 16 Tartaglione G, Rubello D. The evolving methodology to perform limb lymphoscintigraphy: from rest to exercise acquisition protocol. Microvasc Res 2010; 80 (03) 540-544
• 17 Tartaglione G, Visconti G, Bartoletti R. , et al. Stress lymphoscintigraphy for early detection and management of secondary limb lymphedema. Clin Nucl Med 2018; 43 (03) 155-161
• 18 Ebrahim M, Savitcheva I, Axelsson R. Reliability of a scoring system used for qualitative evaluation of lymphoscintigraphic imaging of lower extremities. J Nucl Med Technol 2017
• 19 Visconti G, Albanese R, Salgarello M. Painless indocyanine green lymphography. J Reconstr Microsurg 2017; 33 (03) 225-226
• 20 Michelini S, Paolacci S, Manara E. , et al. Genetic tests in lymphatic vascular malformations and lymphedema. J Med Genet 2018; 55 (04) 222-232
• 21 Cooper G. Genetics and lymphoedema: a future yet to be fully discovered. Br J Community Nurs 2017; 22 (01) 646-648
• 22 Matsumoto K, Shinaoka A, Yamada K, Kimata Y. Exercise-loaded indocyanine green fluorescence lymphangiography for diagnosing lymphedema. J Reconstr Microsurg 2019; 35 (02) 138-144